The study of regularities of the structure – analgesic activity relationship in a series of 4-hydroxy-Nn-(pyridin-2-yl)-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides

I. V. Ukrainets, L. A. Petrushova, O. V. Gorokhova, O. O. Davydenko

Abstract


Continuing the search for new analgesics and with the purpose of revealing the structural-biological regularities, which are important for further studies, the synthesis of a series of 4-hydroxy-N-(pyridin-2-yl)-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides unsubstituted in position 1 has been carried out. The structure of all compounds synthesized has been confirmed by elemental analysis, 1H NMR spectra and mass spectra. Based on a detailed analysis of the mass spectra it has been concluded that 4-hydroxy-N-(pyridin-2-yl)-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides in crystals are inner salts – 3-{[(pyridinium-2-yl)amino]carbonyl}-2,2-dioxo-1H-2,1-benzothiazin-4-olates. It has been noted that spectroscopy of 1H NMR does not allow either to confirm or disprove that in DMSO solution the substances studied exist in the form of inner salts since the signals of the active protons of OH and NHgroups that are important do not appear. According to the results of the pharmacological screening the substances – for example, 3-{[(6-methylpyridinium-2-yl)amino]carbonyl}-2,2-dioxo-1H-2,1-benzothiazin-4-olate – exceeding Piroxicam by the analgesic activity have been found. It has been unequivocally determined that removal of the 1-N-methyl group from the structure of 4-hydroxy-1-methyl-N-(pyridin-2-yl)-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides in general leads to a marked decrease in analgesic properties and may be considered inappropriate.


Keywords


amidation; 2-aminopyridines; 4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides; synthesis; analgesic activity

Full Text:

PDF

References


Kubinyi H. Rossiiskii Khimicheskii Zhurnal – Russian Chemical Journal, 2006, Vol. L, No.2, pp.5-17. http://www.chem.msu.su/rus/journals/jvho/2006-2/5.pdf

Goodman A., McCall J. R., Jacocks H. M., Thompson A., Baden D., Abraham W. M., Bourdelais A. Marine drugs, 2014, Vol. 12, No.4, pp.1839-1858. DOI: 10.3390/md12041839.

Monroy C. A., Doorn J. A., Roman D. L. Chemical research in toxicology, 2013, Vol. 26, No.12, pp.1832-1839. DOI: 10.1021/tx400212q.

Banerjee S. K., Pogolotti A. Jr, Rupley J. A. The Journal of biological chemistry, 1975, Vol. 250, No.20, pp.8260-8266.

Rowland G. W., Schwartz G. G., John E. M., Ingles S. A. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research, 2012, Vol. 27, No.1, pp.187-194. DOI: 10.1002/jbmr.505.

Riverol M., Ordóñez C., Collantes M., DiCaudo C., Peñuelas I., Arbizu J., Marcilla I., Luquin M. R. Neurobiology of disease, 2014, Vol. 62, pp.250-259. DOI: 10.1016/j.nbd.2013.09.014.

Kleemann A., Engel J., Kutscher B., Reichert D. Pharmaceutical Substances: Syntheses, Patents, Applications of the most relevant APIs, 5th ed. Stuttgart, Thieme; 2008, 1800 p.

Ukrainets I. V., Gorokhova O. V., Nidal Amin Jaradat, Petrushova L. A., Mospanova E. V., Savchenkova L. V., Kuz’min V. E., Lyahovsky A. V. 4-Hydroxyquinolin-2-ones and their Close Structural Analogues as a New Source of Highly Effective Pain-killers. In book: Pain and Treatment, Racz G. B. and Noe C. E. (Ed.), Rijeka: InTech, 2014, pp.21-73. DOI: 10.5772/57402. http://www.intechopen.com/articles/show/title/4-hydroxyquinolin-2-ones-and-their-closestructural- analogues-as-a-new-source-of-highly-effective-pa

Ukrainets I. V., Petrushova L. A., Dzyubenko S. P., Sim G. Chemistry of Heterocyclic Compounds, 2014, Vol. 50, No.1, pp.103-110. doi:10.1007/s10593-014-1452-0.

Ukrainets I. V., Petrushova L. A., Dzyubenko S. P., Liu Yangyang. Chemistry of Heterocyclic Compounds, 2014, Vol. 50, No.4, pp.564-572. DOI:10.1007/ s10593-014-1508-1.

Ukrainets I. V., Petrushova L. A, Dzyubenko S. P. Zhurnal Organichnoi ta Farmatsevtichnoi Khimii – Journal of Organic and Pharmaceutical Chemistry, 2014, Vol. 12, No.2(47), pp.53-58.

Petrushova L. A, Ukrainets I. V., Dzyubenko S. P., Grinevich L. A. Zhurnal Organichnoi ta Farmatsevtichnoi Khimii – Journal of Organic and Pharmaceutical Chemistry, 2015, Vol. 13, No.1(50), pp.44-48.

Ukrainets I. V., Petrushova L. A., Dzyubenko S. P. Chemistry of Heterocyclic Compounds, 2013, Vol. 49, No.9, pp.1378-1383. DOI:10.1007/s10593-013-1388-9.

Vogel H. G. Drug Discovery and Evaluation: Pharmacological Assays. – Berlin, Springer; 2008, pp.1014-1016.


GOST Style Citations






DOI: https://doi.org/10.24959/ophcj.15.864

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)